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H. Lundbeck A/S16-Apr-1510 The case for ”One Standard of Evidence” (PhRMA PISC Expert Team White Paper, BASS XV, 2008) The traditional standard of evidence for efficacy of a new treatment T is statistically significant evidence that δ TP > 0 Why should an arbitrarily higher standard of evidence (δ TP > δ > 0) be used when an active-controlled (AC) trial has been used? Preservation margin is arbitrary –Preserving less than p% does not imply ineffectiveness of T –In contrast, δ TP = 0 has a definite objective clinical meaning Requiring a higher standard of evidence for AC trials institutes a regulatory bias in favor of the first drug to be approved (requiring preservation of p% may lead to rejection of T even thought T is better than C)

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H. Lundbeck A/S16-Apr-1511 Hypothetical example: 95% CIs relative to P δ TP =0 p % margin T and C are both superior to P and data suggests that T might be better than C but because C was approved first and T does not meet the p% margin T can’t be approved C vs P T vs P

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H. Lundbeck A/S16-Apr-1514 Metastatic Bladder Cancer cont’d Assuming constancy of δ CP across trials –Gemzar improves survival when added to cisplatin (p=0.035) –Gemzar+cisplatin was estimated to have similar efficacy as MVA+cisplatin (estimated HR=0.96) Why do a test for preservation of effect?

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H. Lundbeck A/S16-Apr-1515 Conclusions One standard of evidence for efficacy should be used – superiority to placebo – regardless of the design used (placebo- or active- controlled) The synthesis method should be used rather than the fixed margin method for better efficiency